Title. Author(s)Kida, Hiroshi. Issue Date Doc URL. Type. File Information. example. Prevention of Infectious Diseases. 2 November 2009.

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1 Title Global Surveillance is the Key for the Control of Zo example Author(s)Kida, Hiroshi Sustainability Weeks 2009 Opening Symposium "Interna CitationRecommendations for Tackling the 5 Challenges of Glo Prevention of Infectious Diseases. 2 November Issue Date Doc URL Type conference presentation File Information 1-1Kida.pdf Instructions for use Hokkaido University Collection of Scholarly and Aca

2 Opening Symposium for the Sustainability Week Hokkaido University, November 2, 2009 Proposals by Hokkaido University for the Sustainable Development Global Surveillance is the Key for the Control of Zoonoses How to control avian, swine, and pandemic influenza as an example Hiroshi Kida Professor, Graduate School of Veterinary Medicine Director, Research Center for Zoonosis Control Head, OIE Reference Laboratory for Avian Influenza Hokkaido University, Sapporo, Japan

3 Are we substantially prepared for pandemic influenza? * Why have the H5N1 HPAIVs persisted in poultry for 12 years? * Why are antigenic variants selected? * Will the HPAIVs returned to migratory birds persist in nature? * How should avian influenza be controlled in poultry? * What are the advantage and disadvantage of the use of vaccines? * Is it OK to forget about H5N1 avian influenza virus strain after the swine-origin H1N1 strain emerged? * Are the measures for the control of seasonal flu satisfactory? Ecology of influenza viruses in nature, birds and mammals; * Origin, evolution, and perpetuation of influenza virus in nature. * Mechanism of the emergence of highly pathogenic avian flu virus and human pandemic strains. * Antigenic variation and genetic reassortment of influenza viruses.

4 Influenza virus particle Hemagglutinin (HA, H subtypes) Neuraminidase (NA, N1-9 subtypes) Envelope

5 Pig Cell Genetic reassortment A/duck/S China/x/67 (H3NX) A/S China/x/67 (H2N2) A/Hong Kong/1/68 (H3N2) Humans

6 Pandemic influenza in humans Highly pathogenic avian influenza

7 Host range, and HA and NA subtypes of influenza A virus H1N1 H1N2 H3N2 H2N3, H3N1, H3N3, H3N8, H4N6, H5N1, H5N2, H9N2 H1N1 H2N2 H3N2 (H2N8,H3N8) H5N1,H7N7, H9N2 H3N8 H7N7 H1-H12 N1-9 H3N8,H5N1 H5N1 H1-16 H1-10 N1-9 N1-9 H3N3 H1-7, H9-16 H4N5 N1-9 H7N7 H1-7, H9-11 N1-4, N6-8 H1N3, H13N2, H13N9 H3N2 H5N1 H10N4 6

8 Duck influenza Each of the known subtypes (H1-16, 16 N1-9) of influenza A virus has been isolated from ducks. In ducks, viruses replicate in the colon, being shed with feces in a week, and non-pathogenic. Water-borne fecal-oral l transmission i Ducks carry and provide viruses during migration and over-wintering. Migratory duck is the NATURAL HOST of influenza A viruses. Kida H et al (1980) Infect Immun

9 Influenza viruses are antigenically and genetically highly conserved in ducks. Viruses replicating in the intestine are not under the serum antibody selection pressure. 40 to 50 % of population of migratory ducks are juvenile birds that hatched in the summer. Preserved in frozen water of the lakes, where they nest in summer, in winter. Kida H et al (1987) Virology; Ito et al (1995) Arch Virol

10 HAs of H3N2 viruses isolated from pigs in southern China Closely related with those of A/Hong Kong/68 (H3N2) and H3 viruses isolated from migratory ducks. Amino acid sequences at the receptor-binding site on the HA indicate either specificity to human or avian type receptors. Both types of receptoer were found on the surface of the epitherial cells lining the upper respiratory tract of pigs. Kida H et al (1988) Virology

11 Influenza viruses isolated from domestic ducks in southern China HAs of influenza viruses isolated from domestic ducks in southern China closely related with those of viruses isolated from migratory ducks, pigs, and A/Hong Kong /68 antigenically and genetically. Each of the viruses was isolated on the Pacific Flyway of migratory ducks. Migratory duck domestic duck pig humans Yasuda J (1991) J Gen Virol

12 Migratory duck A/duck/ xx (H3N?) Domestic duck Pond Virus shedding Genetic reassortment A/Asian/67 (H2N2) 1968 HK A/HongKong/68 g (H3N2) 1918 Spanish virus (H1N1) *1957 Asian virus (H2N2) must have appeared similarly. Rout of transmission of genes of pandemic strains

13 The role of pigs in the emergence of pandemic influenza virus strains Pigs are susceptible to avian influenza viruses of each of the HA subtypes. Genetic reassortants were generated in the cells lining upper respiratory tract of pig upon concurrent infection with mammalian and avian strains. Kida H et al (1994) J Gen Virol

14 Ito T et al (1995) Arch Virol

15 Irkutsk(290) Kenkeme(32) Kharyyalah(146) h(146) 40 Ilands(1321) Yakutsk(232) H3N8 H13N6 Khabarovsk(23) Buotama(51) Elavga(66) Kobyaysky(820) H4N6 H4N9 H11N1 H11N6 H11N9 White Lake(1136) H3N8 Magadan(295) Ptropavlovsk- Kamchatsky(58) Lake Kanicheva(95) Malyshevo(90) Taiwan H1N1 H4N5 H4N6 H7N7 Wakkanai (958) H1N1 H3N8 H5N3 H5N4 H6N2 H6N7 H8N1 H8N3 H9N2 H11N Okazaki K et al (2000) Arch Virol

16 Acquisition of pathogenicity of avian influenza virus in chicken APAIV 6~9 Months LPAIV HPAIV (H5 or H7)

17

18 Return of the HPAIV from domestic poultry to migratory water birds APAIV > 6-9 months LPAIV HPAIV (H5 or H7)

19 HPAI viruses isolated from wild birds in Mongolia A/whooper swan/mongolia/3/05 (H5N1) A/bar-headed goose/mongolia/1/05 (H5N1) A/common goldeneye/mongolia/12/06 (H5N1) Ugii Lake A/whooper swan/mongolia/2/06 (H5N1) Qinghai Lake A/whooper swan/mongolia/2/2009 (H5N1) A/whooper swan/mongolia/9/2009 (H5N1) A/bar-headed goose/mongolia/x53/2009 (H5N1) A/rubby sholduck/mongolia/x42/2009 (H5N1) A/common goldeneye/mongolia/x60/2009 (H5N1)

20 62 Countries where H5N1 HPAIV infections were reported in wild birds, poultry, and both Japan, Republic of Korea, China, Mongolia, Myanmar, Lao PDR, Thailand, Cambodia, Viet Nam, Malaysia, Indonesia, Bangladesh, India, Pakistan; Afghanistan, Iran, Azerbaijan, Georgia, Iraq, Kuwait, Saudi Arabia, Turkey, Israel; Russian Federation, Kazakhstan, Ukraine, Romania, Bulgaria, g,, j, g, q,,, y, ;,,,, g, Albania, Serbia, Hungary, Slovakia, Czech Republic, Croatia, Poland, Slovenia, Bosnia & Herzegovina; Greece, Switzerland, Austria, France, Italy, Germany, Netherlands, Denmark, Sweden, Spain, England, Ireland; Djibouti, Gaza Strip, Egypt, Sudan, Nigeria, Niger, Cameroon, Burkina Faso, Cote d Ivoire

21 Country Deaths / Cases China 25/ 38 Viet Nam 56/111 Indonesia 115/141 Egypt 27/ 87 Cambodia 7/ 8 Lao PDR 2/ 2 Thailand 17/25 Iraq 2/ 3 Azerbaijan 5/ 8 Turkey 4/12 Djibouti 0/ 1 Nigeria 1/ 1 Myanmar 0/ 1 Pakistan 1/ 3 Bangladesh 0/ 1 Total 262/442 As of 24 September 2009

22 Influenza Vaccine for bird flu may prevent manifestation of disease signs and decrease the amount of virus shed, but does not confer protective immunity from infection. is produced with inactivated virus, not live virus. Test and culling or stamping-out policy is recommended for the control o of avian a influenza. Vaccination is not recommended but one of the options applied only under DIVA (differentiating infected from vaccinated animals) based strategy as a tool is, in addition to, not instead of test and culling policy. Country where vaccine is used is not designated as HPAI-free. must lead silent spread of virus.

23 Surveillance of avian influenza in migratory ducks in Mongolia (153 isolates) H2N2 (1) H2N3 (2) Hokkaido (145 isolates) H3N2 (1) H3N6 (11) H1N1 (2) H2N5 (1) H3N8 (75) H4N2 (1) H3N2 (1) H3N5 (2) H3N8 (19) H4N2 (8) H4N3 (1) H4N6 (39) H4N6 (19) H5N3 (5) H4N8 (3) H7N6 (1) H6N1 (7) H6N2 (17) H7N7 (1) H8N1 (1) H6N8 (4) H7N7 (31) H8N4 (1) H9N2 (1) H8N4 (7) H9N2 (2) H10N3 (11) H10N5(3) H9N4 (1) H9N5 (1) H10N7 (1) H10N2 (1) H10N5 (7) H10N6 (1) H10N7 (7) H11N6 (1) H11N9 (1) H12N2 (1) H12N5 (1) China (2 isolates) H3N8 (1) H4N6 (1) Australia (6 isolates) H2N5 (6) from terns

24 > cases >296,471 cases > 3,486 deaths

25 Gene derivation of the swine-origin influenza A (H1N1) virus Classical l swine (derived from the 1918 virus) North American avian Human (H3N2) Eurasian avian-like swine PB2 - North American avian PB1 - Human H3N2 PA - North American avian H1 - Classical swine NP - Classical swine N1 - Eurasian avian-like swine M - Eurasian avian-like swine NS - Classical swine Swine origin Influenza A virus (H1N1) Each of the pandemic strains have been generated in pigs. Genetic reassortment often occurs in birds and pigs. The H1N1 strain is a genuine swine influenza virus. Modified from Novel Swine-Origin Influenza A (H1N1) Virus investigation Team, N Engl J Med, 2009

26 goose turkey duck quail Low Pathogenic AIV pig 6-9Months chickens Human virus HPAIV Apathogenic AIV X Genetic Reassortant virus Pandemic virus HPAI virus and human pandemic virus strains

27 Library of vaccine strain candidates Influenza viruses of 61 combinations of the HA and NA subtypes have been isolated from fecal samples of ducks in Alaska, Siberia, i Mongolia, Taiwan, China, and Japan (black). 83other combinatations have been generated by genetic reassortment procedure in the lab (red).. Isolates from ducks Reassortants Thus, 246 avian influenza viruses of 144 combinations of HA and NA subtypes have been stocked as vaccine strain candidates. Their pathogenicity, antigenicity, genetic information and yield in chicken embryo have been analyzed, databased, and opened for Web site (

28 Are we prepared for pandemic flu? 1. H1 to H16 and N1 to N9 subtypes of influenza A viruses perpetuate in the lakes where ducks nest in nature. 2. Viruses maintained by natural reservoir are antigenically and genetically stasis H2N2 and 1968 H3N2 viruses are reassortants between avian influenza virus and the preceding human strains. 4. Pigs are susceptible to both of avian and mammalian viruses and generate reassortants. 5. Avian viruses of any subtype can contribute genes for reassortants: None of the 16 HA and 9 NA subtypes can be ruled out as potential candidates for future pandemics. 6. Surveillance of swine flu is crucial in the countries where avian flu has not been controlled. 7. Preparedness for pandemic flu should be based on the measures for the control of seasonal flu. 8. Does the swine-origin new H1N1 virus cause seasonal influenza? Then, what should be done for the seasonal flu vaccine?

29 How should influenza be controlled? * Why do the H5N1 HPAIVs have persisted in poultry for 12 years? * Why do these strains show antigenic variation? Misuse of Vaccine * Will the HPAIVs that returned to migratory birds persist in nature? * How should avian influenza be controlled in poultry? Stamping-out without misuse of vaccine is only way, so far. * What are the advantage and disadvantage of the use of vaccines? * Are the measures for the control of seasonal flu satisfactory? The measures how to control pandemic influenza should be based on the measures for the control of seasonal influenza. * The swine-origin new H1N1 virus should cause seasonal influenza. Vaccine for seasonal influenza should contain the new H1N1 virus antigen. Global surveillance and seasonal flu control measure-based strategy

30 For the control of zoonoses Identification of natural host & elucidation of the route of transmission CONTROL OF ZOONOSES Development of measures for diagnosis and prevention Clarification of the molecular basis of pathogenesis Zoonoses should be controlled when the novel field of science is established by the collaboration with and fusion of Veterinary Medicine, Medicine, Public Health, Ecology, Epidemiology, and Computer Science.

31 Research Center for the Control of Zoonoses Veterinary Medicine Medicine Ministry of Agriculture, Forestry and Fisheries Ministry of Education, Culture, Sports, Science and Technology Ministry of Health, Labour and Welfare Hokkaido University Research Center for Zoonosis Control Transmission of Pathogens Prevention and therapeutics of diseases in livestock Ecology of zoonotic pathogens Prevention and control of zoonoses Maintenance and improvement of human and public health OIE WHO Ministry of the Environment Species conservation of wild animals Department of Dept of Molecular Dept of Dept of Collaboration Hokudai Center for Global Epidemiology Pathobiology Bioresources and Education Zns Control in Zambia Identification of natural host animals of zoonotic pathogens Diagnosis of zoonotic infections and development of detection methods Preservation and supply of pathogens, cells, genes and animal strains Coordination of collaboration programs with international and domestic organizations Identification of natural host animals and transmission routes of zoonotic pathogens